Abstract
Indoleamine 2,3-dioxygenase (IDO; EC 1.13.11.42) is a rate-limiting enzyme involved in the catabolism of tryptophan, which is an essential amino acid. It is induced under pathological conditions, such as the presence of viral infections or tumour cells. This enzyme is induced by IFN-γ in the mouse rectal carcinoma cell line CMT-93. It is known that both 1-methyl-l-tryptophan (1-MT) and methylthiohydantoin-dl-tryptophan (MTH-trp) are tryptophan analogues, and are authentic inhibitors of the enzymatic activity of IDO. In this study, we examined the effects of both 1-MT and MTH-trp on the IFN-γ inducible IDO expression of CMT-93. As a result, the IFN-γ inducible IDO mRNA and the protein levels in CMT-93 were suppressed by 1-MT and MTH-trp, independently. Moreover, tryptophan (Trp), as a substrate of IDO, also suppressed IDO induction by IFN-γ at the transcriptional level. These results suggest that 1-MT and MTH-trp are as inhibitors of IDO enzymatic activity, and Trp suppresses IDO induction by IFN-γ at the transcriptional level.
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Abbreviations
- IDO:
-
Indoleamine 2,3-dioxygenase
- IFN:
-
Interferon
- 1-MT:
-
1-Methyl-l-tryptophan
- MTH-trp:
-
Methylthiohydantoin-dl-tryptophan
References
Burke F, Knowles RG, East N, Balkwill FR (1995) The role of indoleamine 2,3-dioxygenase in the anti-tumor activity of human interferon-gamma in vivo. Int J Cancer 60:115–122
Chon SY, Hassanain HH, Pine R, Gupta SL (1995) Involvement of two regulatory elements in interferon-gamma-regulated expression of human indoleamine 2,3-dioxygenase gene. J Interferon Cytokine Res 15:517–526
Friberg M, Jennings R, Alsarraj M, Dessureault S, Cantor A, Extermann M, Mellow AL, Munn DH, Antonia SJ (2002) Indoleamine 2,3-dioxygenase contributes to tumor cell evasion of T cell-mediated rejection. Int J Cancer 101:151–155
Hassanain HH, Chon SY, Gupta SL (1993) Differential regulation of human indolamine 2,3-dioxygenase gene expression by interferons-gamma and -alpha Analysis of the regulatory region of the gene and identification of an interferon-gamma-inducible DNA-binding factor. J Biol Chem 268:5077–5084
Kadoya A, Tone S, Maeda H, Minatogawa Y, Kido R (1992) Gene structure of human indoleamine 2,3-dioxygenase. Biochem Biophys Res Commun 189:530–536
Konan KV, Taylor MW (1996) Importance of the two interferon-stimulated response element (ISRE) sequences in the regulation of the human indoleamine 2,3-dioxygenase gene. J Biol Chem 271:19140–19145
Mellor AL, Munn DH (2004) IDO expression by dendritic cells: tolerance and tryptophan catabolism. Nat Rev Immunol 4:762–774
Morita T, Saito K, Takemura M, Maekawa N, Fujigaki S, Fujii H, Wada H, Takeuchi S, Noma A, Seishima M (2001) 3-Hydroxyanthranilic acid, an l-tryptophan metabolite, induces apoptosis in monocyte-derived cells stimulated by interferon-gamma. Ann Clin Biochem 38:242–251
Muller AJ, DuHadaway JB, Donover PS, Sutanto-Ward E (2005) Prendergast GC inhibition of indoleamine 2,3-dioxygenase, an immunoregulatory target of the cancer suppression gene Bin1, potentiates cancer chemotherapy. Nat Med 11:312–319
Munn DH, Zhou M, Attwood JT, Bondarev I, Conway SJ, Marshall B, Brown C, Mellor AL (1998) Prevention of allogeneic fetal rejection by tryptophan catabolism. Science 281:1191–1193
Munn DH, Shafizadeh E, Attwood JT, Bondarev I, Pashine A, Mellor AL (1999) Inhibition of T cell proliferation by macrophage tryptophan catabolism. J Exp Med 189:1363–1372
Overbergh L, Valckx D, Waer M, Mathieu C (1999) Quantification of murine cytokine mRNAs using real time quantitative reverse transcriptase PCR. Cytokine 11:305–312
Shimizu T, Nomiyama S, Hirata F, Hayaishi O (1978) Indoleamine 2,3-dioxygenase. J Biol Chem 253:4700–4706
Suzuki S, Tone S, Takikawa O, Kubo T, Kohno I, Minatogawa Y (2001) Expression of indoleamine 2,3-dioxygenase and tryptophan 2,3-dioxygenase in early concepti. Biochem J 355:425–429
Takikawa O, Kuroiwa T, Yamazaki F, Kido R (1988) Mechanism of interference-γ action. J Biol Chem 263:2041–2048
Takikawa O, Yoshida R, Kido R, Hayaishi O (1986) Tryptophan degradation in mice initiated by indoleamine 2,3-dioxygenase. J Biol Chem 261:3648–3653
Taylor MW, Feng G (1991) Relationship between interferon-gamma, indoleamine 2,3-dioxygenase, and tryptophan catabolism. FASEB J 5:2516–2522
Towbin H, Staehlin T, Gordon J (1979) Electrophoretic transfer of proteins from polyacrylamide gels to nitrocellulose sheets: procedure and some applications. Proc Natl Acad Sci USA 76:4350–4354
Werner ER, Bitterlich B, Fuchs D, Hausen A, Reibnegger G, Szabo G, Dierich MP, Wachter H (1987) Human macrophages degrade tryptophan upon induction by interferon-gamma. Life Sci 41:273–280
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This study was supported in part by Research Project Grants (Nos. 17-509 and 18-502) from Kawasaki Medical School.
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Okamoto, T., Toné, S., Kanouchi, H. et al. Transcriptional regulation of indoleamine 2,3-dioxygenase (IDO) by tryptophan and its analogue. Cytotechnology 54, 107–113 (2007). https://doi.org/10.1007/s10616-007-9081-4
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DOI: https://doi.org/10.1007/s10616-007-9081-4